Abstract
Background
Maternal syphilis causes poor birth outcomes including congenital syphilis. Testing and treatment of partners prevents re-infection, however strategies to improve partner attendance are failing. This study aimed to determine the effectiveness of 3 partner notification strategies.
Methods
Pregnant women with a positive, point-of-care treponemal test at three antenatal clinics (ANC) in Kampala, Uganda were randomized 1:1:1 to receive a) notification slips (NS) (standard of care) b) NS and text messages (SMS) c) NS and phone calls. The primary outcome was the proportion of partners who attended ANC and were treated for syphilis.
Results
Between 2015-2016 17,130 pregnant women were screened; 601(3.5%) with a positive treponemal result were identified and 442 enrolled. Of 81/442 (18.3%) partners (23/153 (15.1%), 31/145 (21.5%) and 27/147 (18.5%) in the NS only, NS+SMS, and NS+phone call arms respectively attended ANC for follow up; no statistical difference was seen between the arms. 12% of women attended ANC with their male partner; increasing over time. Partner non-treatment was independently associated with adverse birth outcomes OR (95%CI) 2.75 (2.36 – 3.21), P<0.001.
Conclusions
Only 18.3% of partners of pregnant women who tested positive for syphilis received treatment. Female partners of non-attendant men had worse birth outcomes. Encouraging men to accompany women to ANC and testing both may address the urgent need to treat partners of pregnant women in sub-Saharan Africa to reduce poor fetal outcomes.
Keywords: Maternal syphilis, Mother to child transmission, partner notification, mobile phones
Summary text for the online Table of Contents
This is the first reported randomized controlled trial of partner notification approaches to antenatal syphilis in sub-Saharan Africa. There was low male partner uptake of syphilis testing and treatment (overall 18%) irrespective of strategy used (notification slip, SMS, voice call), but over the course of the study more men attended ANC with their partners. Treatment of male partners to prevent reinfection of women remains challenging and may increase the risk of poor birth outcomes.
Background
Annually, there are nearly 1 million cases of maternal syphilis globally (1) causing adverse outcomes (low birth weight, stillbirth, preterm delivery and congenital syphilis) in up to 50% of untreated pregnancies(2, 3). Screening and treatment with single-dose benzathine penicillin for pregnant women is effective, inexpensive and has been demonstrated to be cost effective (4, 5). In sub-Saharan Africa (SSA), it is estimated that universal antenatal screening could reduce the annual number of stillbirths, neonatal deaths, and congenital syphilis cases by up to 64,000, 25,000 and 32,000 respectively. Newer syphilis and combined HIV-syphilis point-of-care-tests (POCT) help to increase syphilis testing in pregnancy across the region (6). Unless infected male partners of pregnant mothers are treated, re-infection later in the index pregnancy or subsequent pregnancies may occur. This is especially the case in SSA countries with high birth rates and limited access to sexually transmitted infection (STI) services. In Uganda, national health surveys show that 1.8% of adults aged 15-49 years have syphilis, and in 1% of couples both are infected (7). Antenatal clinic (ANC) estimates are slightly higher at 2.1 – 3.0%; neonatal mortality is 2.5% with syphilis an important driver of adverse maternofetal outcomes (8).
Partner notification (PN) has been used since the 19th century for STI control(9) and aims to ‘close the loop’ of infection by ensuring all potentially infected partners of the index case are identified and treated. Different PN options are shown in Table 1. PN approaches have been extensively studied in resource-rich settings (10, 11) but there is little documentation of PN in Africa especially for syphilis. A 2013 Cochrane review of PN randomized control trials (RCT) (12) examined 24 studies, 4 of which were conducted in Africa. Only one, completed more than 20 years ago in the USA(13), examined PN strategies in syphilis. PN in resource limited settings (RLS) such as SSA is mainly accomplished through index patient notification, as provider-oriented PN is costly (14, 15); this approach is encouraged by the WHO(16). Willingness of index patients to notify their partners has been shown to be high in SSA (58% in Uganda (17), 50% in Rwanda (18) and 93% in Zimbabwe (15)). Furthermore, studies on client counselling in Zambia, (19) and Zimbabwe (15) increased PN for STIs. In Uganda lower rates (25% to 34%) of partners attending for treatment have been observed (17, 20), including 34.5% attendance observed by our team at the Infectious Diseases Institute (IDI), Kampala for syphilis PN (21). A 2010 review of PN strategies in RLS recommended index patient PN with counselling, but recognized the difficulty of implementation in such settings with limited counsellors and lack of privacy (14). A post appointment follow-up interaction with index cases (in person or by phone) has shown to increase uptake of partner notification in gonorrhea (22), and is a standard practice in HIV partner notification in sub-Saharan Africa (including Uganda)(23).
Table 1 –
Types of partner notification
| Type of partner notification | Contacting index case | Follow up |
|---|---|---|
| Provider oriented methods | Health care worker (HCW) or other third party | |
| Patient oriented | Index patients | |
| Mixed methods | Index patients | HCW if index patient fails to notify |
| Expedited partner therapy (EPT) | Index case provided with anti-biotics to give to partner [10] | Possible HCW follow up |
Alum et. al also proposed studies using mobile phone technology to support PN (14), which is attractive given the high levels of access to mobile phones in SSA. Uganda has a mobile phone network coverage of over 90% and 48% of inhabitants have a mobile phone subscription (24). However, as with all mobile (m) health strategies, many studies are in pilot form and efficacy data are lacking (11, 25). In order for PN through short messaging services (SMS or text messages) to be viable ethically, confidentiality issues must be overcome (26, 27). SMS to index patients is ethically uncomplicated and may be an inexpensive way to encourage index patients to inform their partners in RLS, as has proven beneficial in high-income countries (28).
We designed the Syphilis Treatment Of Partners (STOP) trial to provide a low cost, partially-automated addition to improve on existing index case PN strategies of the Uganda Ministry of Health (paper notification slips). The approach was based on experience gained in PN at IDI with targeted counseling and SOC (58% informed their partner) (21), as well as other African studies on index case PN (15, 29). The opportunity presented by increased mobile phone penetration could allow for inexpensive follow-up calls and automated SMS with a view of increasing partner attendance without large time and financial resource burdens. However, we wished to avoid contacting partners directly due to confidentiality issues, so we added an additional post-test contact to the index case to increase PN. We anticipated that many of the barriers and facilitators in previous published STI and HIV work would be similar for syphilis. We included both phone and SMS because we speculated that deferential attitudes to HCPs might make HCP-initiated phone calls more effective than SMS, but SMS are cheaper and therefore worth exploring. The objective was to compare the proportion of partners who reported to the clinic for syphilis testing (and treatment) when syphilis-positive pregnant women were given only PN slips (SOC)), compared to SOC plus SMS reminders or SOC plus phone call reminders.
Methods
Participant recruitment
Between February 2015 and February 2016 pregnant women were identified in ANCs at Mulago Hospital and Kasangati Health Centre IV, both are Ministry of Health-run centers with busy ANCs, and the IDI Adult Infectious Disease Clinic, a private, not-for-profit clinic with attached ANC in Kampala, Uganda. Potential participants were identified and approached by study staff. Screening was undertaken for syphilis using point-of-care (POC) lateral flow tests (SD Bioline, Standard Diagnostics, Inc, Republic of Korea). HIV status was established by self-report and if unknown, women were offered testing using the rapid sequential algorithm. Those found to be positive were referred to HIV services if not previously in care. Women with a positive pregnancy test and treponemal antibody rapid POCT were offered study inclusion. Other inclusion criteria were age>18 years or 14-17 years and being a mature and emancipated minor (as defined by Ugandan National Science and Technology guidelines), having a known sexual partner, having access to a cell phone, and being willing and able to use and receive SMS or phone calls. Criteria for exclusion included illiteracy, inability to use a mobile phone and confirmed neurosyphilis. Potential participants were offered information by study nurses and counselors and examined to exclude neurosyphilis. Treatment was with 2.4 million units intramuscular benzathine penicillin G (BPG) (in case of allergy, azithromycin 2 gm orally). Participants gave informed written consent for randomization and for temporary specimen storage (blood). Serum was batched for rapid plasma reagin (RPR) testing with titer confirmation at the Walter Reed Research laboratory in Kampala.
Women who attended with their partners were offered testing for HIV and syphilis, but were not included in the study, as male partners were notified and treated for syphilis on the same day if their partner had a positive test.
Randomization
Participants were randomized by a computer-generated block randomization algorithm of different sized blocks with a 1:1:1 ratio by an independent member of the IDI statistics team. The randomization schedule was provided to the site in a box of sequentially numbered, opaque, sealed envelopes to the enrolling study nurses. The sequential randomization codes were recorded on the study entry case report form to ensure randomization adherence. All participants were given a written PN slip.
Intervention
The 3 study arms consisted of:
Standard of care:
The PN slip was given to the pregnant female participant on the day she received her syphilis test results. She was asked to give it to her sexual partner(s) and encourage them to attend the STI clinic for syphilis management. The PN slip contained only a code number, but no identifiable features.
SMS reminders and notification slip for partner screening:
In addition to SOC, participants received weekly SMS reminders to encourage their partners to attend the STI clinic for syphilis testing for up to 8 weeks after the woman’s initial positive syphilis test. The participant ID code number was written on the notification slip which partners were asked to bring with them to the clinic and in the SMS reminders.
Phone call reminders and notification slip for partner screening:
In addition to SOC, participants received a weekly phone call for up to 8 weeks after initial syphilis diagnosis from a nurse to remind them to encourage their partners to attend the STI clinic for syphilis testing. The participant ID code number was written on the notification slip which partners were asked to return to clinic and was also given to the participant via the nurse calls.
Script for messages is available in supplementary Table 1.
Follow up
All participants were encouraged to attend ANC every 4 weeks until delivery. Notification slips were in duplicate; one given to the pregnant woman and one held in the clinic. On partner return, the slips were matched and used for linkage. The one postpartum study visit was conducted within 3 months of the end of pregnancy to assess clinical status, signs, and symptoms, antibiotic side effects, and adverse pregnancy outcomes as reported by the mothers, and to undertake serum storage. When possible mothers’ knowledge of partner treatment (place, type of treatment etc.) were captured. When the mother failed to attend, the study team performed a follow up phone call or home visit to the woman or recorded next of kin. If the mother had experienced a stillbirth or neonatal death in this pregnancy, she was offered counseling. If a baby had signs or symptoms of congenital syphilis, a referral was made to the National referral hospital for medical evaluation.
When the male partner attended the STI clinic as a result of a notification, informed consent to collect study-related data was conducted. Men underwent testing for syphilis using a rapid treponemal antibody test followed by RPR confirmation. All men attending were given syphilis treatment (as above) on the same visit regardless of their syphilis results as per MOH guidelines. Any partner attendance reported through verbal confirmation by the mother or physical attendance by the partner for treatment between time of registration and maternal post-natal visit was included in the analysis.
Women received a small travel reimbursement ($8USD), but this was not given to male partners to avoid a financial incentive for attendance.
Sample Size
The sample size was calculated using data from the IDI clinic located within urban Kampala where 220 pregnant women are seen at the ANC per month with 5.1% syphilis positivity (21), and the Mulago Hospital ANC where on average 2000 pregnant women are seen monthly with 2.4% syphilis positivity (8). We estimated, based on a previous study at IDI with targeted counseling and SOC, that 50% of women would notify their partners and that 60% of those notified would attend clinic in the SOC arm (overall 30% of male partners)(21). We hypothesized that if counselling and PN slip alone resulted in 30% partner attendance then additional interventions with reminders (SMS, calls) would have a positive effect resulting in increased partner attendance (1 interview = 13% partner attendance, vs more than 1=60% for gonorrhea(22)). In order to show a 50% increase in the proportion of partners of women attending for testing and treatment in the intervention arms (45% of male partners overall), we estimated a sample size of 292 women per arm with a total of 876 participants. To account for multiple comparisons of the effect of each of the interventions with the SOC arm, a type 1 error (alpha) of 1.67% was set.
Analysis
The primary outcome was the proportion of partners who presented at the clinic and received syphilis testing/treatment. A Pearson’s Chi-square statistic was used to test for differences in the three arms. Secondarily, we compared proportions of men who tested positive for syphilis, proportion who received syphilis treatment from the ANC and those reported by their spouse/partner to have received treatment elsewhere using Chi-square statistic. For some analyses we combined birth outcomes into positive outcomes (live mother and baby) and negative, rarer, outcomes (miscarriage, still birth, preterm labor, birth defects, neonatal death as reported by the enrolled mothers). A multivariable logistic regression model with robust standard errors was used to establish factors associated with negative pregnancy outcomes. In this model, the notification arm was the primary exposure variable while age, marital status, employment, and treatment of partner for syphilis were considered potential confounders. All analyses were performed using STATA 15.1 (College Station, Texas, USA).
Ethical approvals
Ethical approval was obtained from the Ugandan Joint Clinical Research Centre Institutional Review Board (IRB), the Uganda National Council for Science and Technology (HS1681), and the Johns Hopkins IRB (NA_00012998/CR00015330). The trial was registered at clinicaltrials.gov (NCT02262390). The study adhered to CONSORT guidelines in methods and reporting.
Results
Syphilis screening
A total of 17,130 participants were interviewed between January 2015 and February 2016 (Figure 1) and follow up was completed by April 2017. The median age of pregnant women screened was 25 years (interquartile range (IQR): 22-28), 15,094 (88.1%) were married, and median parity was 2 (IQR: 1-4). Six hundred and one (3.5%) tested treponemal antibody positive. Of 16,805 whose HIV status was known, 808 (4.8%) were HIV-positive. Syphilis prevalence was higher among HIV-positive women 67/808 (8.3%) compared to HIV-negative women 535/16322 (3.3%). A fifth (20.2%) reported a negative outcome in a previous pregnancy; 20.1% who were syphilis negative, compared to 23.3% who were syphilis positive (p<0.001) (supplementary table 2). Of 601 with positive syphilis tests, 71 (11.8%) were not enrolled due to lack of phones, 55 (9.2%) due to attendance with partner and 33 (5.5%) for other reasons (Figure 1). The number of women attending with their partner for first antenatal visit increased over time (supplemental Figure 1). Of 442 pregnant women enrolled, all were rapid test positive, 404 (91.4%) were RPR positive, 36 (8.1%) RPR negative and two RPR results (0.45%) were missing. Of the positive RPRs at enrolment 156/404 (38.6%) were ≥1:8. All women who were treponemal antibody positive received BPG.
Figure 1 –
Consort diagram
Enrolment
Overall, 442 pregnant women were enrolled with 152 (34.4%) in the partner notification slip, 144 (32.6%) in the slip + SMS and 146 (33.0%) in the slip + phone call –arms respectively. The majority 362/442 (81.9%) were enrolled from the Mulago site, 185 (41.9%) had primary (41.8%) or secondary 220 (49.8%) level education. A majority were in their second trimester 251/442 (56.8%), and 28/442 (6.3%) were HIV positive (Table 2).
Table 2:
Baseline demographic and clinical characteristics of enrolled mothers
| Variable | Notification slip (N=152) | Slip + SMS reminder (N=144) | Slip + nurse Phone call (N=146) | Overall Population (N=442) |
|---|---|---|---|---|
| Site | ||||
| IDI AIDC1 | 4 (2.6%) | 4 (2.8%) | 2 (1.4%) | 10 (2.3%) |
| Mulago | 129 (84.9%) | 118 (81.9%) | 115 (78.8%) | 362 (81.9%) |
| Kasangati | 19 (12.5%) | 22 (15.3%) | 29 (19.9%) | 70 (15.8%) |
| Age in Years | ||||
| Median (IQR) | 26 (24,29) | 27 (24,30) | 26 (23,29) | 26 (23,30) |
| Marital status | ||||
| Monogamous marriage | 111 (73.0%) | 96 (66.7%) | 119 (81.5%) | 326 (73.8%) |
| Polygamous marriage | 35 (23.0%) | 39 (27.1%) | 23 (15.7%) | 97 (22.0%) |
| Separated/divorced | 0 (0.0%) | 1 (0.7%) | 0 (0.0%) | 1 (0.2%) |
| Single regular partner | 5 (3.3%) | 7 (4.9%) | 4 (2.7%) | 16 (3.6%) |
| Single irregular partner | 1 (0.7%) | 1 (0.7%) | 0 (0.0%) | 2 (0.5%) |
| Education Level | ||||
| None | 0 (0.0%) | 1 (0.7%) | 0 (0.0%) | 1 (0.2%) |
| Primary level | 54 (35.5%) | 67 (46.5%) | 64 (43.8%) | 185 (41.9%) |
| Secondary level | 84 (55.3%) | 68 (47.2%) | 68(46.6%) | 220 (49.8%) |
| Tertiary | 13 (8.6%) | 7 (4.9%) | 14 (9.6%) | 34 (7.7%) |
| Missing | 1 (0.7%) | 1 (0.7%) | 0 (0.0%) | 2 (0.5%) |
| Currently employed | ||||
| Yes | 70 (46.0%) | 88 (61.1%) | 77 (52.7%) | 235 (53.2%) |
| HIV Status | ||||
| Negative | 138 (90.8%) | 135 (93.7%) | 136 (93.2%) | 409 (92.5%) |
| Positive | 11 (7.2%) | 7 (4.9%) | 10 (6.8%) | 28 (6.3%) |
| Missing | 3 (2.0%) | 2 (1.4%) | 0 (0.0%) | 5 (1.1%) |
| Gravid | ||||
| 1 | 14 (9.2%) | 12 (8.3%) | 18 (12.3%) | 44 (9.9%) |
| 2 | 36 (23.7%) | 30 (20.8%) | 33 (22.6%) | 99 (22.4%) |
| 3+ | 102 (67.1%) | 102 (70.8%) | 95 (65.1%) | 299 (67.7%) |
| Pregnancy planned | ||||
| Yes | 120 (79.0%) | 115 (80.4%) | 129 (88.4%) | 364 (82.5%) |
| Pregnancy Trimester | ||||
| 1st Trimester | 9 (5.9%) | 10 (6.9%) | 7 (4.8%) | 26 (5.9%) |
| 2nd Trimester | 83 (54.6%) | 76 (52.8%) | 92 (63.0%) | 251 (56.8%) |
| 3rd Trimester | 60 (39.5%) | 58 (40.3%) | 47 (22.2%) | 165(37.3%) |
Data represents number and percentages in parentheses except for age. IDI AIDC: Infectious Diseases Institute-Adult Infectious Diseases Clinic, IQR: Interquartile Range
Post enrolment partner attendance
Post-enrolment partner attendance at study sites was very low at 18.2% (81/442). The PN slip arm had 23/152 (15.1%) partners returning, the SMS arm 31/144 (21.5%) and the phone call arm 27/ 146 (18.5%). There was no significant differences between study-documented post-enrolment partner attendance by method of partner notification Person’s Chi-square p=0.363 (Table 3). An interim futility analysis suggested that there would be no significant difference seen in the arms of the study with the original sample, which led to stopping the enrolment before reaching the original sample size.
Table 3:
Partner attendance by study notification arm
| Randomization arm | ||||
|---|---|---|---|---|
| Notification slip (N = 152) | Slip + SMS reminder (N = 144) | Slip + SMS Slip + nurse reminder phone call(N = 146) | Overall Population (N = 442) | |
| Partner attendance | 23/152 (15.1%) | 31/144(21.5%) | 27/146 (18.5%) | 81/442 (18.3%) |
| IDI AIDC (n = 10) |
0/4 (0.0%) | 1/4 (25.0%) | 1/2 (50.0%) | 2/10 (20.0%) |
| Mulago (n = 362) |
16/129 (12.4%) | 25/118 (21.2%) | 22 /115 (19.1%) | 63/362 (17.4%) |
| Kasangati (n = 70) |
7/19 (36.8%) | 5/22 (22.7%) | 4/29 (13.8%) | 16/70 (22.8%) |
| Days between delivery of notification slip to woman and partner clinic visit Median (IQR) |
20 (5,35) |
20 (6,42) |
22 (7,30) |
21 (6,35) |
Characteristics of male partner who attended are shown in table 4. The mother was not aware of partner clinic attendance for 12/81 (14.8%) men who reported for treatment at study sites. Of the men that attended clinic study sites 21/81 (25.9%) tested positive for syphilis; there was no difference in the syphilis positive rates of the male partners attending by arm (p = 0.267). An additional 17 mothers reported that their partners had attended a non-study clinic or health facility for syphilis treatment, which increased the total rate to 98/442 (22.2%) of male partners accessing treatment. When these men were included in the analysis, 27/98 (22.2%) were in the notification slip, 35/98 (35.7%) the SMS, and 36/98 (36.7%) the phone call arms (p=0.151).
Table 4:
Demographic characteristics of male partners enrolled in the study
| Variable | Male partner not diagnosed with Syphilis (N=59) | Male partner diagnosed with Syphilis (N=19) | Overall Male partner Population (N=781) |
|---|---|---|---|
| Site | |||
| IDI AIDC | 2 (3.9%) | 0 (0.0%) | 2 (2.6%) |
| Mulago | 45 (76.3%) | 15 (79.0%) | 60 (76.9%) |
| Kasangati | 12 (20.3%) | 4 (21.0%) | 16 (20.5%) |
| Age in Years | |||
| Median (IQR) | 30 (26,39) | 31 (28,38) | 26 (23,30) |
| Marital status | |||
| Monogamous marriage | 47 (79.7%) | 14 (73.7%) | 61 (78.2%) |
| Polygamous marriage | 12 (20.3%) | 5 (26.3%) | 17 (21.8%) |
| Education Level | |||
| None | 1 (1.7%) | 1 (5.2%) | 2 (2.6%) |
| Primary level | 21 (35.6%) | 6 (31.6%) | 27 (34.6%) |
| Secondary level | 27 (45.7%) | 8 (42.1%) | 35 (44.8%) |
| Tertiary | 10 (17.0%) | 3 (15.8%) | 13 (16.7%) |
| Post tertiary | 0 (0.0%) | 1 (5.2%) | 1 (1.3%) |
| Currently employed | |||
| Yes | 57 (96.6%) | 19 (100.0%) | 76 (97.4%) |
| History of HIV testing | |||
| Negative | 52 (88.1%) | 18 (94.7%) | 70 (89.7%) |
| Positive | 4 (6.8%) | 1 (5.3%) | 5 (6.5%) |
| Never tested | 3 (5.1%) | 0 (0.0%) | 3 (3.8%) |
: Three partners who returned to the clinic had missing Syphilis test results
Mother and baby outcomes
A total of 396 (89.6%) enrolled women were followed up through a phone call (n=133 (33.6%)) or in-person (n=263 (66.4%)) visit; 136 (34.3%) from the slip only arm, 131(33.1%) from the SMS and 129 (32.6%) from phone call arms). Of these, only 22/396 did not give the notification slip to their partner (10/136 [7.4%] in the notification slip arm, 4/131 [3.1%] in the SMS arm and 8/129 [6.2%] in the phone call arm). Among women who were followed up, 372 (93.9%) had a healthy delivery at term, 2 (0.5%) had pre-term births, 13 (3.3%) spontaneous/ induced abortions, 9 (2.3%) had stillbirths. In total 24 (6.1%) negative pregnancy outcomes (preterm births, abortion, stillbirth, and miscarriages) were observed; 7/136 (5.2%) in the notification slip, 11/131 (8.4%) in the SMS, and 6/129 (4.6%) in the phone call arms respectively, (p=0.386). Among the women whose partners received treatment for syphilis, 2/86 (2.3%) experienced negative pregnancy outcomes compared to 22/310 (7.1%) in those whose partners were not treated, p=0.127. In the multivariable logistic regression model (table 5), the risk of having a negative pregnancy outcome increased under the following conditions: with every 5 year age increase Odds Ratio (OR) [95% Confidence Interval (CI)] 1.55 [1.33 – 1.79], p=0.005 among women in polygamous-compared to monogamous marriages the (OR 2.59 [1.12 – 5.99]), p=0.025 in women whose partners were untreated for syphilis (OR 2.75 [2.36 – 3.21]), p<0.001. For unemployed women the OR was 1.19 [1.02 – 1.40] p=0.028 (Table 5). In a sensitivity analysis where all women who were lost-to-follow up were considered to have negative pregnancy outcomes, the results were similar.
Table 5:
A multiple logistic regression model showing factors associated with negative pregnancy outcomes among women who returned for follow-up
| Variable | Adjusted Odds Ratio (95% Confidence Interval) | P Value |
|---|---|---|
| Age every 5-year increase | 1.55 (1.33 – 1.79) | <0.001 |
| Marital status | ||
| Monogamous marriage | 1.00 | |
| Polygamous marriage | 2.59 (1.12 – 5.99) | 0.025 |
| Single/divorced | 2.94 (0.04 – 226.40) | 0.625 |
| Employment status | ||
| Currently employed | 1.00 | |
| Not employed | 1.19 (1.02 – 1.40) | 0.028 |
| Partner treated for syphilis | ||
| Yes | 1.00 | |
| No | 2.75 (2.36 – 3.21) | <0.001 |
| Notification arm | ||
| Slip only | 1.00 | |
| Slip + SMS | 1.80 (0.96 – 3.38) | 0.068 |
| Slip + Phone call | 0.99 (0.50 – 2.01) | 0.996 |
Note: Model adjusted for reproductive history and HIV status. Correlation between sites was accounted for using robust standard errors. Negative outcomes include (preterm births, abortion, stillbirth, and miscarriages)
Discussion
This is the first reported RCT of PN approaches to antenatal syphilis in SSA and the first major trial of syphilis PN in 20 years. It is large, screening over 17,000 pregnant women and recruiting over 400 female participants. Syphilis sero-positivity rates were high at 3.5%. It tested SOC index case notification against mobile phone based methods which are cheap and widely available in SSA. Overall, our study in Ugandan ANC achieved a post-enrolment partner attendance of 18.2% with no significant difference seen between the method used (notification slip, call or SMS). A major finding was that partner non-treatment was independently and significantly associated with adverse birth outcomes on multivariate analysis.
Our study demonstrated much lower partner attendance than previously published work. In Kenya, two partner notification studies showed 67% and 58% of notified partners reported for STI treatment (29). In Uganda, partner attendance rates have been lower at 25% to 34.5% (17, 20, 21). This low attendance rate was a major limitation of this study. A futility analysis was undertaken, which led to enrolment being capped at 422/876 planned enrolments; resources were not available to dramatically increase the sample size required to adequately power the primary outcome. There are several reasons for low attendance which highlight limitations of the study including mothers not informing the male partner, male partner informed but did not attend, male partner attended but did not tell the mother, and male partners more likely to take treatment being screened out. These will be explored here.
Previous published studies on PN for STIs in RLS revealed barriers including lack of knowledge of STIs, stigma, fear of domestic violence, fear of revealing extra-matrimonial partners or inability to contact casual partners (14). Therefore, numerous cultural and systemic barriers exist at all stages of the pathway, from the point where the woman is diagnosed with syphilis to informing her partner(s); their clinic attendance and receiving appropriate testing and treatment. An additional limitation of this study and a key ‘lesson learnt’ is that we perhaps did not go far enough to break down some of these barriers despite our previous work in this area(21). Ideally we should have undertaken syphilis-specific intervention development work with pregnant women, but our “low resource approach” did not allow for dedicated counselling time. We had anticipated that a clinic-generated SMS shown to a partner or a witnessed telephone call may have facilitated discussions between partners. In a qualitative sub-study (30) we showed poor partner communication, stigma and fear of intimate partner violence (IPC) as barriers to partner notification.
Two recent studies have shown that those with an STI are supportive of index case partner notification. In South Africa 91% of men in a high risk group would prefer notification of an STI by slip from their partner but only 62.7% felt that an SMS from health care worker was acceptable (31). In Uganda, index case partner notification was deemed highly acceptable by most groups, and health care providers voiced concerns about limited time, resources, and training for provider-assisted approaches(32). These would suggest that index cases are prepared to inform their partners, but getting partners to attend is the issue. A limitation of the study is that we did not collect data on who had told their partner, just if their partner had attended or not.
The qualitative sub-study (30) identified limited knowledge on syphilis as the main reason for lack of partner attendance. In order to strengthen our approach, a series of staged information messages about syphilis via text message or voice call, rather than just notification reminders may have had more impact and is worthy of future study. Another issue highlighted by the qualitative work was the poor communication between partners. Notably, 15% of men attended for treatment without notifying their pregnant partner. This could also have contributed to an underestimate of number of men attending for treatment.
The reduced rate we saw may be due to the exclusion of women who attended ANC with their partner; overall we excluded 12% (74/601) of syphilis positive women whose partners attended with them, as they were tested and treated for syphilis on the same day. The increase in male partner attendance over time demonstrates that the ongoing MOH strategy encouraging male partner attendance at ANC had a positive effect during the course of this study. Therefore, we hypothesize that widespread availability of syphilis and HIV testing for mothers and their partners along with patient educational interventions could improve syphilis screening uptake. It is striking that there were relatively low rates of syphilis in the men who did attend for testing (25.9%), challenging the assumption that untreated male partners are the predominant driver of syphilis in pregnancy. We speculate that those men who did attend were more willing and/or better able to engage with the health system and systematically different from those who did not attend.
There is a possibility of unmeasured confounding by site selection; there are disparities in care across health care settings in Uganda generally, but inclusion of three different settings, all with low partner attendance rates may indicate the problem is generalized across different settings. Other obstacles include refurbishment of Mulago Hospital and consequent relocation of the ANC presented difficulties for mothers to attend follow-up appointments within study limits. This resulted in missing post-treatment RPR data in many, making conclusions about longitudinal RPR results impossible. Previous work in Tanzania showed that women with high syphilis RPR titres (>1:8) indicating active syphilis had 25% stillbirth rate compared to those with low titres(3); however it is not possible to infer if negative pregnancy outcomes were likely due to congenital syphilis in our study.
Since the study was undertaken, Uganda has embraced assisted partner notification for HIV testing along with WHO encouragement of this approach(33). Index cases found HIV positive enter into an agreement with health care workers, that they will notify their partners in a certain time period. If they have not done this by the time they are contacted the health worker will undertake contact partner notification if the index case is in agreement (34). They are supported with counselling to assist with communicating to their partner, including strategies such as role play if necessary. With this regulatory change, the study team feel that assisted partner notification may be a preferable method to undertake syphilis partner notification moving forward. However, in our qualitative work mothers were concerned about intimate partner violence to mothers who disclose partner details or admit to having an STI, so this needs to be seriously considered if men are to be contacted directly by HCPs (30). Regulatory frameworks covering non-HIV STIs would be welcome to support health care workers in choosing the best method of PN including assisted partner notification.
Conclusion
This study screened over 17000 pregnant women and by the end of the study over 12% attended clinic with their male partners. Treatment of male partners is extremely important, as demonstrated by more negative birth outcomes in women with untreated partners; the prospect of a healthy infant will motivate both men and women. SMS and phone calls remain potentially useful and underused tools in STI partner management in RLS, but the technology has yet to be maximally evaluated. Further studies to stop the cycle of re-infection of mothers and congenital syphilis are needed and the role of men in the solution cannot be overlooked if progress is to be made.
Supplementary Material
Acknowledgements -
We wish to thank the patients and staff of the Mulago and Kasangati ANC clinics, the STI clinic at Mulago, and the IDI Sexual and Reproductive Health Clinic.
Competing interests: RMPR receives grant funding through the Infectious Diseases Institute from Janssen, the Pharmaceuticals Company of Johnson and Johnson. No others disclosed.
Funding: This study was funded by Foundation for the National Institutes of Health. 5U54EB007958 to Professor Charlotte Gaydos. The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Abbreviations
- STI
sexually transmitted infections
- DALY
Disability Adjusted Life Years
- HCP
Health care provider
- PN
Partner notification
- IDI
Infectious Diseases Institute
- POCT
point-of-care tests
- ANC
antenatal clinic/care
- MOH
Ministry of Health
Footnotes
Ethics approval and consent to participate: Ethical approval was obtained from the Ugandan Joint Clinical Research Centre Institutional Review Board (IRB), the Uganda National Council for Science and Technology (HS1681), and the Johns Hopkins IRB (NA_00012998 / CR00015330). The trial was registered at clinicaltrials.gov (NCT02262390). Any person aged 14-17 years and being a mature and emancipated minor was able to provide their own informed consent as defined by Ugandan National Science and Technology guidelines. Nonetheless, no participants under age 16 were enrolled in the study.
Consent for publication: NA
Availability of data and material: As this is clinical data the source documents will not be available online, but authors can be contacted for more information
Trial registration: Clinicaltrials.gov NCT02262390. Date of registration. October 13, 2014
Authors’ information: NA
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